administered in the two sites, comparable dosage (i.e., plaque forming 
units (pfu)/cell) will be given to the epithelial cells of all sites. 
(3) The maximum titer of adenovirus that can be repeatedly achieved in 
production is lxlO 11 to 5xlO n pfu/ml. This, together with the 
limitation of volume, puts an upper limit on dose. 
Conclusions Regarding Design of the Protocol 
(1) Use different patients for ascending doses, with n=2 at each dose. 
Continue to add n=2 patient groups until the maximum dose is reached 
or toxicity is observed. 
(2) Start with a total dose in the range that has been used to assess the 
responses of humans to replication competent adenovirus . For a 60 kg 
male (CF individuals tend to have less body mass than normals) , start 
with titers of 10 6 pfu/ml (total dose to the lung with 20 ml volume 
will be 2xl0 7 pfu/60 kg = 3 . 3xl0 5 pfu/kg) for the first two individu- 
als and increase in groups of n=2 until the highest dose (20 ml x 10 11 
pfu/ml-60 kg = 3.3xl0 10 pfu/kg) is reached. 
Study Population 
Constraints 
(1) It can be argued that rather than starting with individuals with CF, 
it would be much easier to determine if there are any adverse effects 
from the Ad vector or the CFTR cDNA if the initial study population 
were normal volunteers. First, regarding the Ad vectors, this would 
not be different from evaluating live adenovirus or adenovirus 
vaccines in normal humans, studies which have been extensively 
evaluated and reported in the literature (see Table 5.2-A). Second, 
the Ad vector to be utilized in this study, AdCFTR, expresses a normal 
CFTR cDNA. Potential adverse effects generated in response to 
expression of the CFTR protein must be balanced against potential 
benefits to individuals. The potential benefit in CF individuals will 
be amelioration or cure of the respiratory manifestations of the 
disease. In contrast, while there is no experimental evidence to argue 
that AdCFTR, in the same dosages, would be harmful to normals, no 
benefit in normals would be expected. Within the CF population, 
individuals with at least one allele known to produce the CFTR protein 
will be selected, as these individuals will be less likely to respond 
immunologically to expression of the exogenous gene. 
(2) As it is a goal of the protocol to be able to demonstrate conversion 
of airway epithelial cells from an abnormal CF phenotype to a normal 
phenotype, it is mandatory that the CF genotype is known. 
Conclusions Regarding Design of the Protocol 
(1) The subjects will have CF as identified by conventional clinical 
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